A role for mDia, a Rho-regulated actin nucleator, in tangential migration of interneuron precursors

Abstract

In brain development, distinct types of migration, radial migration and tangential migration, are shown by excitatory and inhibitory neurons, respectively. Whether these two types of migration operate by similar cellular mechanisms remains unclear. We examined neuronal migration in mice deficient in mDia1 (also known as Diap1) and mDia3 (also known as Diap2), which encode the Rho-regulated actin nucleators mammalian diaphanous homolog 1 (mDia1) and mDia3. mDia deficiency impaired tangential migration of cortical and olfactory inhibitory interneurons, whereas radial migration and consequent layer formation of cortical excitatory neurons were unaffected. mDia-deficient neuroblasts exhibited reduced separation of the centrosome from the nucleus and retarded nuclear translocation. Concomitantly, anterograde F-actin movement and F-actin condensation at the rear, which occur during centrosomal and nuclear movement of wild-type cells, respectively, were impaired in mDia-deficient neuroblasts. Blockade of Rho-associated protein kinase (ROCK), which regulates myosin II, also impaired nuclear translocation. These results suggest that Rho signaling via mDia and ROCK critically regulates nuclear translocation through F-actin dynamics in tangential migration, whereas this mechanism is dispensable in radial migration.

Speed control for neuronal migration in the postnatal brain by Gmip-mediated local inactivation of RhoA

“…These results suggest that a periodic change in RhoA activation in the proximal leading process has an important role in migrating neurons. Consistent with this finding, a recent report showed that new V-SVZ neurons deficient in mDia, a Rho-regulated actin nucleator, exhibit impaired migration towards the OB 24 , which is a phenocopy of the DN-RhoA cells described here ( Supplementary Fig. 6b,c).…”

“…In support of this idea, inactivation of the RhoA signal by an mDia deficiency results in the abnormal regulation of the actin cytoskeleton in the proximal leading process, resulting in defective movement of the centrosome and cell soma towards the swelling 24 . Thus, Gmip-mediated regulation of RhoA activity may control the stride distance and frequency of the somatic saltatory movement through cytoskeletal rearrangements, significantly impacting the average speed of the long-distance migration of new neurons in the postnatal RMS (Supplementary Fig.…”

“…A recent study suggests that Rho signalling via mDia (mammalian diaphanous homologue) and ROCK/Rho-kinase (Rho-associated protein kinase) regulates F-actin dynamics in these cellular compartments to promote the saltatory movement of the soma of new neurons migrating from the V-SVZ to OB 24 , suggesting that F-actin dynamics and organization through the regulation of Rho signalling is essential for neuronal migration. The activity of Rho family small GTPases is tightly regulated by three groups of proteins: guanine nucleotide exchange factors, GTPase-activating proteins (GAPs) and guanine nucleotide dissociation inhibitors [25][26][27] .…”

Dynamics of the leading process, nucleus, and Golgi apparatus of migrating cortical interneurons in living mouse embryos

“…Additionally, the centrosome, along with the Golgi, is frequently found within swellings of fixed neurons (3,6,37). These swellings have been seen to move forward in migrating neurons before nucleokinesis (3,4,38,39), suggesting that cytoplasmic swellings associated with the Golgi/centrosome complex are involved in pulling the nucleus (3,22). Conversely, evidence suggesting other force-generating mechanism(s) for nucleokinesis is also accumulating.…”

Homozygous loss of DIAPH1 is a novel cause of microcephaly in humans

“…Whole-exome sequencing (WES) and targeted sequencing analyses identified a rare, nonsense, homozygous sequence variant c.2332C4T (p.Gln778*, RefSeq NM_005219.4) in the gene DIAPH1 (mouse symbol is Diap1) (MIM 602121) encoding the mammalian diaphanous-related formin, mDia1. The encoded protein has previously been implicated in neuronal migration of cortical interneurons, 4 autosomal hearing loss, 5 and myelodysplasia. 6 Depending upon the cell type and position in the cell cycle, mDia1 has been shown to localize to the cell cortex, trafficking endosomes, cleavage furrow, mid-bodies, and centrosomes, the cytoplasmic microtubule-organizing center crucial for cell division.…”